Supported nano gold catalyzed three-component coupling reactions of amines, dichloromethane and terminal alkynes (AHA)

Article abstract of DOI:10.1016/j.tetlet.2015.01.132

A simple and efficient method for the synthesis of pharmaceutically relevant propargylamines through one-pot three-component coupling reactions of amines, CH₂Cl₂, and terminal alkynes (AHA) using nano Au/CeO₂ as a heteroge

Full text of DOI:10.1016/j.tetlet.2015.01.132

Accepted Manuscript
Supported nano gold catalyzed three-component coupling reactions of amines,
dichloromethane and terminal alkynes (AHA)
Amina Berrichi, Redouane Bachir, Mohamed Benabdallah, Noureddine
Choukchou-Braham
PII:
S0040-4039(15)00170-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.01.132
TETL 45802
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
2 October 2014
31 December 2014
20 January 2015
Please cite this article as: Berrichi, A., Bachir, R., Benabdallah, M., Choukchou-Braham, N., Supported nano gold
catalyzed three-component coupling reactions of amines, dichloromethane and terminal alkynes (AHA),
Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.01.132
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Graphical Abstract
Supported nano gold catalyzed three
Leave this area blank for abstract info.
-component coupling reactions of amines,
dichloromethane and terminal alkynes (AHA)
Amina Berrichi, Redouane Bachir, Mohamed Benabdallah,
Noureddine Choukchou-Braham
2% Au/CeO2
base, solvent
Ph
Et2NH
Ph
CH2Cl2
NEt2

2
Tetrahedron Letters
journal homepage: www.elsevier.com
Supported nano gold catalyzed three-component coupling reactions of amines,
dichloromethane and terminal alkynes (AHA)
Amina Berrichi, Redouane Bachira*, Mohamed Benabdallah, Noureddine Choukchou-Braham
a
Laboratory of Catalysis and Synthesis in Organic Chemistry, BP 119, University of Tlemcen, Algeria
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple and efficient method for the synthesis of pharmaceutically relevant
propargylamines through one-pot three-component coupling reactions of amines,
CH2Cl2 and terminal alkynes (AHA) using nano Au/CeO2 as a heterogeneous catalyst
is reported. The catalyst is characterized by DRX, DR-UV visible spectroscopy and
TEM. Gold particles are regularly distributed on ceria and range in size from 2-4 nm.
2014 Elsevier Ltd. All rights reserved
Available online
Keywords:
Propargylamine
coupling reaction
AHA
Heterogeneous catalysis
nano gold
Multicomponent reactions (MCRs) involve the construction and
cleavage of carbon–carbon and carbon–heteroatom bonds. These
reactions are simple, fast and efficient for chemical synthesis.
They have considerable economic and ecological benefits.1
Pharmaceutically relevant propargylamines2 can be produced by
MCRs. Propargylamines are key intermediates for the
preparation of many biologically active nitrogen compounds such
as β-lactams3 and therapeutic drugs.4, 5
(Scheme 1). Significant progress has been made by using
homogeneous catalysts. Copper salts,45, 46 nano-In2O3,47 Fe salts,48
AgOAc49 and gold salts50 are the most important. However,
compared to various transition-metal-catalyzed A3 coupling
reactions, the catalysts employed for AHA couplings are limited.
The activation of the C-Cl bond has been studied using
homogeneous catalysis, but there are no reports on the coupling
of CH2Cl2, alkynes and amines employing heterogeneous
supported gold catalysts. In this work, a supported nano gold
catalyst, Au/CeO2, is used in AHA coupling reactions.
Three-component coupling reactions of amines, aldehydes, and
alkynes (A3) are used to synthesize propargylamines via C–H
activation.6 Different catalysts have been used for these reactions
NR1R2
7-17
29
such as copper-based catalysts,
Ag,18-23 Zn,24-28 NiCl2, Fe
HNR1R2
+
CH2Cl2
Ph
+
33
34-37
nanoparticles,30,31 FeCl3,32 BiCl3 and gold salts.
Syntheses
Ph
of propargylamines under heterogeneous catalysis are
particularly attractive as they allow the production and ready
separation of large quantities of products using small amounts of
catalysts. Supported nano gold particles, Au/CeO2,38 Au/Al2O3,
Scheme 1. The AHA coupling reaction
39
Preparation of catalyst by deposition precipitation with urea
NAP-Mg-Au,40 Au/PMO-IL,41 Au/IRMOF-342 and Au/ZnO43
The catalyst, 2% Au/CeO2, was prepared by deposition
precipitation with urea (DPU) as previously described.51,52
Commercial nano CeO2 (1.97 g) was dispersed in 200 mL of
distilled water under stirring until the temperature reached 80 °C,
then 8 mL (2% Au) of HAuCl4.3H2O (10g/L) and 1.2 g of urea
were added, and the mixture was stirred for 16 hours. The
resulting solid was dried at 80 °C overnight, then charcterized by
DR-UV visible spectroscopy, XRD and TEM.
have been used as catalysts for A3 coupling reactions of
benzaldehyde, alkynes, and piperidine.
Dichloromethane is a major industrial solvent44 and is commonly
used as a medium for MCRs. It can also be used as a source of
carbon and replace aldehydes in three-component coupling
reactions. Alkynes, halomethane and amine coupling reactions
can be achieved and are commonly known as AHA processes
———
*
Corresponding author Tel+ 213 43 213198; Fax + 213 43 213198
Email: redouane_bachir@hotmail.com;
redouane.bachir@mail.univ-tlemcen.dz

3
The AHA coupling procedure:
differences compared to the CeO2 spectrum. This suggests that
A terminal alkyne (2 mmol), an amine (2.2 mmol), CH2Cl2 (1.5
mmol), a base (2 mmol), and Au/CeO2 (80 mg) were mixed with
3 ml of solvent. After 24 hours, the reaction mixture was diluted
with CH2Cl2 and the catalyst was recovered by centrifugation.
The mixture was extracted with water/CH2Cl2 and dried over
Na2SO4. Evaporation of the solvent furnished the crude product
which was subjected to column chromatography. The products
were characterized by NMR and FTIR spectroscopy.
the gold particles are very small, hence, they cannot be observed
by XRD.
Catalyst Characterization
Figure 2: DR-UV Visible spectra of CeO2 (_ _) and Au/CeO2 (__)
The catalyst was next characterized by DR-UV Visible
spectroscopy. Figure 2 shows a band at 570 nm in the spectrum
of Au/CeO2. This band is characteristic of small gold
nanoparticles on the surface of ceria. It is related to the plasmon
effects of gold nanoparticles.54 Finally, we characterized the
catalyst by TEM. A typical image (Figure 3a) shows gold nano
particles distributed on ceria. Moreover, the histogram of the
particle size distribution (Figure 3b) has a Gaussian shape
indicating that the majority of the gold particles have sizes
between 2 nm and 4 nm and a mean size of 4.8 nm.
Figure 1: XRD spectra of (a) CeO2 and (b) Au/CeO2
First the CeO2 support and the Au/CeO2 catalyst were
characterized by XRD. The XRD patterns are shown in Figure 1.
In Figure 1a, all the peaks match well with the typical spectrum
of ceria.53 The Au/CeO2 spectrum (Figure 1b) reveals no
Figure 3: TEM image of 2%Au/CeO2 and the particle size distributions determined by statistical analysis of different TEM images

4
Table 1: Optimization of the reaction conditions for the synthesis of propargylamine derivatives catalyzed by 2% Au/CeO2
2% Au/CeO2
Ph
Et2NH
Ph
CH2Cl2
base, solvent
NEt2
Entry
1
Solvent
Base
Temp (°C)
65
Yield (%)f
trace
trace
24
DMSO
DMSO
no solvent
DMSO
H2O
DABCOa
DABCOb
DABCO
DABCO
DABCO
DABCO
DABCOc
DABCO
DABCOd
DABCO
DABCO
DABCO
DABCO
DABCO
DBU
2
65
3
65
4
65
30
5
65
44
6
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
65
53
7
65
53
8
25
trace
trace
trace
50
9
25
10
11
12
13
14
15
16
17
18
40
120
65
39
1,4-dioxane
CH2Cl2
65
trace
41
65
CH3CN
CH3CN
CH3CN
CH3CN
65
40
K2CO3
65
24
NH4OAc
no basee
65
30
65
20
Reaction conditions: phenylacetylene (2.0 mmol), Et2NH (2.2 mmol), CH2Cl2 (23.5 mmol), base (2.0 mmol), solvent (3 ml), Au/CeO2 (80 mg),
65 °C, 24 h
a No catalyst. b The reaction was catalyzed by CeO2 before gold deposition. c After 48-72 h. d After 72 h. e After 36 h. f Isolated yields after
column chromatography.
Synthesis of propargylamines by AHA coupling reactions
Moreover, the reaction proceeded more efficiently in the
presence of organic bases such as DABCO (1,4-diazabicyclo[
2.2.2]octane) and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)
(Table 1, entries 6, 7, 11, 12, 14 and 15), probably due to their
high solubility in organic systems. The inorganic bases K2CO3
and NH4OAc were found to be less reactive (Table 1, entries 16
and 17). It should be noted that the yield decreased in the absence
of a base (entry 18).
Initially, to optimize the reaction conditions, diethylamine,
phenylacetylene and dichloromethane were used as model
substrates, and the influence of various reaction variables such as
the base, solvent and temperature on the reaction was
investigated (Table 1).
The results show that polar solvents (H2O, CH3CN) gave good
yields (entries 5 and 6) compared to DMF, 1,4-dioxane and
CH2Cl2 (entries 12, 13 and 14). Without a solvent the yield of the
propargylamine decreased (entry 3).
We also examined the temperature effect at room temperature, 40
°C, 65 °C and 120 °C. It was observed that this reaction was
susceptible to temperature changes. The results show clearly that
a temperature of 65 °C was needed for the reaction to occur. At

5
room temperature and 40 °C the yield of product was very low
(Table 1, entries 8-10), but increased to 53% at 65 °C (Table 1,
entries 6 and 7). This may be attributed to the fact that the
reaction is slower at low temperatures, however, an increase in
temperature generates a high pressure inside the reaction vessel,
resulting in a higher reaction rate.55-57
using the optimized conditions. The catalyst was separated from
the reaction mixture by centrifugation, washed with CH2Cl2 and
water, dried at room temperature and reused. The results in Table
3 show that the yields were similar until the third cycle. The
decrease of the catalyst activity is probably due to HCl being
released during the reaction, which probably modifies the ceria
and therefore the interaction between gold nanoparticles and
ceria.
The optimum reaction conditions adopted are: phenylacetylene
(2.0 mmol), diethylamine (2.2 mmol), CH2Cl2 (23.5 mmol),
DABCO (2.0 mmol), 2% Au/CeO2 (80 mg), CH3CN (3 mL), 65
°C, 24 h.
Mechanism
According to studies reported in the literature49,50,57 and our
results, the catalytic mechanism for the AHA three-component
coupling reaction with CH2Cl2, phenylacetylene and amines is
proposed in Scheme 2.
In order to show that the method can be used to produce different
propargylamines, we varied the nature of the amine while
keeping phenylacetylene as the terminal alkyne. Thus, various
secondary amines (2a-d) were used in the AHA three-component
coupling reaction with CH2Cl2 and phenylacetylene using the
optimum reaction conditions (Table 2). Propargylamine yields of
up to 60% were obtained. These results are very significant
compared with the studies on AHA couplings using
homogeneous catalysts.
The reaction of CH2Cl2 and amine 2 gives a chloro-N,N-R1R2-
methammonium chloride salt 4, which is known as a Mannich
reaction intermediate.55 This compound produces chloro-N,N-
R1R2-methanamine 5 by elimination of HCl. Finally, 5 reacts
with an adsorbed molecule of phenylacetylene 1 on the catalyst
surface to give the corresponding propargylamine.
The reusability of the catalyst was studied in the AHA coupling
reaction of phenylacetylene, dichloromethane and diethylamine
Table 2: Three-component coupling between phenylacetylene, CH2Cl2 and amines catalyzed by 2% Au/CeO2
Reaction conditions: phenylacetylene (2.0 mmol), amine (2.2 mmol), CH2Cl2 (23.5 mmol), DABCO (2.0 mmol), CH3CN (3 ml),
Au/CeO2 (80 mg), 65 °C, 24 h. a Yield after 48 h

6
Table3: Reusability of the 2%Au/ CeO2 catalyst
Run
1
2
Yield (%)
53
50
30
3
Reaction conditions: phenylacetylene (2.0 mmol), Et2NH (2.2 mmol), CH2Cl2 (23.5 mmol), DABCO (2.0 mmol), CH3CN (3 ml), Au/CeO2 (80
mg), 65 °C, 24 h
NR1R2
1
3
Au/CeO2
NR1R2
Cl
5
HCl
Au/CeO2
CH2Cl
HNR1R2
HNR1R2
CH2Cl2
Cl
H
2
4
Scheme 2: A plausible mechanism for the synthesis of propargylamines via the coupling of amines, CH2Cl2, and terminal
alkynes using 2% Au/CeO2
In conclusion, a heterogeneous supported nano gold catalyst has
been used for the first time to synthesize propargylamines via a
one-pot, three-component coupling reaction of phenylacetylene,
CH2Cl2 (instead of aldehydes) and different secondary amines.
Indeed, supported gold nanoparticles can activate the C-H bond
of a terminal alkyne and the C-Cl bond of CH2Cl2. The catalyst
can be reused up to three times
11 Sharghi, H.; Khalifeh, R.; Moeini, F.; Beyzavi, M. H.; Beni,
A. S.; Doroodmand, M. M. J. Iran. Chem. Soc. 2011, 8, S89.
12 Luz, I.; Llabres i Xamena, F. X.; Corma, A. J. Catal. 2012,
285, 285.
13 Jose Albaladejo, M.; Alonso, F.; Moglie, Y.; Yus, M. Eur. J.
Org. Chem. 2012, 3093.
14 Ramu, V. G.; Bordoloi, A.; Nagaiah, T. C.; Schuhmann, W.;
Muhler, M.; Cabrele, C. Appl. Catal., A 2012, 431, 88.
15 Naeimi, H.; Moradian, M. Appl. Catal., A 2013, 467, 400.
16 Srinivas, M.; Srinivasu, P.; Bhargava, S. K.; Kantam, M. L.
Catal. Today 2013, 208, 66.
References
1
2
Singh, M. S.; Chowdhury, S. RSC Adv. 2012, 2, 4547.
Peshkov, V. A.; Pereshivko, O. P.; Van der Eycken, E. V.
Chem. Soc. Rev. 2012, 41, 3790.
3
4
Indrani B.; Atsushi O.; Bimal K. B. Heterocycl. Lett. 2011,
Vol. 1 83.
Bolea, I.; Gella, A.; Unzeta, M. J. Neural Transm. 2013, 120,
893.
Carvell, H. W.; Lawson, J. Biochem. Pharm 1974, 23, 629.
Li, P.; Wang, L. Tetrahedron 2007, 63, 5455.
Choudary, B. M.; Sridhar, C.; Kantam, M. L.; Sreedhar, B.
Tetrahedron Lett. 2004, 45, 7319.
Gommermann, N.; Knochel, P. Tetrahedron 2005, 61, 11418.
Sreedhar, B.; Reddy, P. S.; Krishna, C. S. V.; Babu, P. V.
Tetrahedron Lett. 2007, 48, 7882.
17 Dulle, J.; Thirunavukkarasu, K.; Mittelmeijer-Hazeleger, M.
C.; Andreeva, D. V.; Shiju, N. R.; Rothenberg, G. Green
Chem. 2013, 15, 1238.
18 Li, Z. G.; Wei, C. M.; Chen, L.; Varma, R. S.; Li, C. J.
Tetrahedron Lett. 2004, 45, 2443.
19 Reddy, K. M.; Babu, N. S.; Suryanarayana, I.; Prasad, P. S.
S.; Lingaiah, N. Tetrahedron Lett. 2006, 47, 7563.
20 Yan, W.; Wang, R.; Xu, Z.; Xu, J.; Lin, L.; Shen, Z.; Zhou,
Y. J. Mol. Catal. A: Chem. 2006, 255, 81.
21 Li, P.; Wang, L.; Zhang, Y.; Wang, M. Tetrahedron Lett.
2008, 49, 6650.
5
6
7
8
9
10 Kantam, M. L.; Laha, S.; Yadav, J.; Bhargava, S.
22 Maggi, R.; Bello, A.; Oro, C.; Sartori, G.; Soldi, L.
Tetrahedron 2008, 64, 1435.
Tetrahedron Lett. 2008, 49, 3083.
23 Zhou, Y.; He, T.; Wang, Z. ARKIVOC 2008, (xiii), 80.

7
24 Ramu, E.; Varala, R.; Sreelatha, N.; Adapa, S. R.
Tetrahedron Lett. 2007, 48, 7184.
We thank DGRST and the University of Tlemcen for funding
this work
25 Kantam, M. L.; Balasubrahmanyam, V.; Kumar, K. B. S.;
Venkanna, G. T. Tetrahedron Lett. 2007, 48, 7332.
26 Mukhopadhyay, C.; Rana, S. Catal. Commun. 2009, 11, 285.
27 Satyanarayana, K. V. V.; Ramaiah, P. A.; Murty, Y. L. N.;
Chandra, M. R.; Pammi, S. V. N. Catal. Commun. 2012, 25,
50.
28 Eagalapati, N. P.; Rajack, A.; Murthy, Y. L. N. J. Mol. Catal.
A: Chem. 2014, 381, 126.
29 Samai, S.; Nandi, G. C.; Singh, M. S. Tetrahedron Lett. 2010,
51, 5555.
30 Sreedhar, B.; Kumar, A. S.; Reddy, P. S. Tetrahedron Lett.
2010, 51, 1891.
31 Zeng, T.; Chen, W.-W.; Cirtiu, C. M.; Moores, A.; Song, G.;
Li, C.-J. Green Chem. 2010, 12, 570.
32 Chen, W.-W.; Nguyen, R. V.; Li, C.-J. Tetrahedron Lett.
2009, 50, 2895.
33 Teimouri, A.; Chermahini, A. N.; Narimani, M. Bull. Korean
Chem. Soc. 2012, 33, 1556.
34 Lo, V. K.-Y.; Kung, K. K.-Y.; Wong, M.-K.; Che, C.-M. J.
Organomet. Chem. 2009, 694, 583.
35 Xiao, F.; Chen, Y.; Liu, Y.; Wang, J. Tetrahedron 2008, 64,
2755.
36 Price, G. A.; Brisdon, A. K.; Flower, K. R.; Pritchard, R. G.;
Quayle, P. Tetrahedron Lett. 2014, 55, 151.
37 Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem. Int. Ed
2006, 45, 7896.
38 Zhang, X.; Corma, A. Angew. Chem. Int. Ed. 2008, 47, 4358.
39 Abahmane, L.; Koehler, J. M.; Gross, G. A. Chem. Eur. J.
2011, 17, 3005.
40 Layek, K.; Chakravarti, R.; Kantam, M. L.; Maheswaran, H.;
Vinu, A. Green Chem. 2011, 13, 2878.
41 Karimi, B.; Gholinejad, M.; Khorasani, M. Chem. Commun.
2012, 48, 8961.
42 Liu, L.; Zhang, X.; Gao, J.; Xu, C. Green Chem. 2012, 14,
1710.
43 Gonzalez-Bejar, M.; Peters, K.; Hallett-Tapley, G. L.;
Grenier, M.; Scaiano, J. C. Chem. Commun. 2013, 49, 1732.
44 Stromeyer, S. A.; Winkelbauer, W.; Kohler, H.; Cook, A. M.;
Leisinger, T. Biochem. Pharm 1991, 2, 129.
45 Yu, D.; Zhang, Y. Adv. Synth. Catal. 2011, 353, 163.
46 Lin, Z.; Yu, D.; Zhang, Y. Tetrahedron Lett. 2011, 52, 4967.
47 Rahman, M.; Bagdi, A. K.; Majee, A.; Hajra, A. Tetrahedron
Lett. 2011, 52, 4437.
48 Gao, J.; Song, Q.-W.; He, L.-N.; Yang, Z.-Z.; Dou, X.-Y.
Chem. Commun. 2012, 48, 2024.
49 Chen, X.; Chen, T.; Zhou, Y.; Au, C.-T.; Han, L.-B.; Yin, S.-
F. Org. Biomol. Chem. 2014, 12, 247.
50 Aguilar, D.; Contel, M.; Urriolabeitia, E. P. Chem. Eur. J.
2010, 16, 9287.
51 Ameur N. ; Berrichi A. ; Bedrane S.; Bachir R. Adv. Mater.
Res. 2014, 856, 48.
52 Ameur, N.; Bedrane, S.; Bachir, R.; Choukchou-Braham, A.
J. Mol. Catal. A: Chem. 2013, 374, 1.
53 Zhu, L.; Letaief, S.; Liu, Y.; Gervais, F.; Detellier, C. Appl.
Clay Sci. 2009, 43, 439.
54 Rawat, V. S.; Bathini, T.; Govardan, S.; Sreedhar, B. Org.
Biomol. Chem. 2014, 12, 6725.
55 Nevstad, G. O.; Songstad, J. Acta Chem. Scand. B Org.
Chem. Biochem 1984, 38, 469.
56 Hallett-Tapley, G. L.; Crites, C. O. L.; González-Béjar, M.;
McGilvray, K. L.; Netto-Ferreira, J. C.; Scaiano, J. C. J.
Photochem. Photobiol. A Chem. 2011, 224, 8.
57 Anand, N.; Ramudu, P.; Reddy, K. H. P.; Seeth, K.; Rao, R.;
Jagadeesh, B.; Babu, V. S. P.; Burri, D. R. Appl. Catal., A
2013, 454, 119.
Acknowledgments

2% Au/CeO2
HNR1R2
Ph
Ph
CH2Cl2
CH3CN, DABCO, 65 °C, 24 h
NR1R2
1a
2a-2d
3a-3d
Entry
Amine
Product
Yield(%)
Ph
Ph
1
2
Et2NH
53
55
2a
2b
3a
3b
NEt2
O
N
N
H
O
Ph
Ph
3
4
53
2c
3c
N
N
H
59-60a
2d
3d
N
N
H
Reaction conditions: Alkyne (2.0 mmol), amine (2.2 mmol), CH2Cl2 (23.5 mmol), DABCO (2.0 mmol), CH3CN (3 ml),
Au/CeO2 (80 mg), 65 °C, 24 h. a yield after 48h